Affiliations: 1: Department of Oral Biology, School of Dental Medicine, State University of New York at Buffalo, Buffalo, NY 14214;
2: Department of Oral Biology, School of Dental Medicine, State University of New York at Buffalo, Buffalo, NY 14214

Immunohistochemical studies identified serous cells of the glandular acini as the cells responsible for production of salivary histatins. Histatins exhibit fungicidal activity against several Candida species, Aspergillus fumigatus, some strains of Saccharomyces cerevisiae, and Cryptococcus neoformans. Studies of levels of salivary histatins in vivo show large intersubject variation in both the concentrations of histatins and their rates of degradation. The total concentration of histatins in whole saliva is balanced between secretion of new proteins and removal of “older” proteins by degradation. Endocytosis was initially suggested as a means of histatin cellular entry based upon the observation that bafilomycin, an inhibitor of endosomal acidification, significantly decreased antifungal activity. Confocal imaging of C. albicans cells showed that some histatin 5 was localized to the vacuole but that cells containing only vacuolar histatin were viable. The cell wall of C. albicans is a thick multilayered structure of glucans, chitin, and mannoproteins that protects cells from osmotic stress and maintains structural integrity. Animal and human clinical studies to evaluate histatins as topical agents in prevention of gingivitis reported therapeutic efficacy without adverse side effects. The major requirements for effective use of salt-insensitive fungicidal peptides are selective and specific binding and uptake by candidal cells, efficacy at low concentrations that allow rapid eradication of yeast pathogens within the ionic strength of saliva, and minimal fungal resistance.

Model of histatin binding and uptake by C. albicans. Both cell wall polysaccharides and Ssa2 proteins play an important role in initial capture and binding of extracellular histatins. These proteins are facilitators that transfer cell wall-bound histatins (and other cationic peptides) to the actual importer mechanism involving active transport via Dur permeases and energy dependent endocytosis. doi:10.1128/9781555817176.ch13.f3

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FIGURE 3

Model of histatin binding and uptake by C. albicans. Both cell wall polysaccharides and Ssa2 proteins play an important role in initial capture and binding of extracellular histatins. These proteins are facilitators that transfer cell wall-bound histatins (and other cationic peptides) to the actual importer mechanism involving active transport via Dur permeases and energy dependent endocytosis. doi:10.1128/9781555817176.ch13.f3

Histatin intracellular trafficking utilizes two pathways in C. albicans. Two distinct routes of intracellular trafficking of histatin 5 are observed. Endocytotic trafficking directly to the vacuole is slower (top), while cytoplasm-to-vacuole trafficking is more rapid (bottom). Histatin 5 is labeled with fluorescein isothiocyanate for visualization using confocal microscopy (39). doi:10.1128/9781555817176.ch13.f4

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FIGURE 4

Histatin intracellular trafficking utilizes two pathways in C. albicans. Two distinct routes of intracellular trafficking of histatin 5 are observed. Endocytotic trafficking directly to the vacuole is slower (top), while cytoplasm-to-vacuole trafficking is more rapid (bottom). Histatin 5 is labeled with fluorescein isothiocyanate for visualization using confocal microscopy (39). doi:10.1128/9781555817176.ch13.f4

3. Baev,D.,, X.Li, and, M.Edgerton.2001.Genetically engineered human salivary histatin genes are functional in Candida albicans: development of a new system for studying histatin candidacidal activity.Microbiology147:3323–3334.

54. O’Brien-Simpson,N. M.,, S.G. Dashper, and, E.C. Reynolds.1998.Histatin 5 is a substrate and not an inhibitor of the Arg- and Lys-specific proteinases of Porphyromonas gingivalis.Biochem. Biophys. Res. Commun.250:474–478.